The present invention provides a solvent based process for the isolation of 14.beta.-hydroxy-10-deacetyl baccatin-III (14.beta.-OH-DAB) which is a very important precursor for the synthesis of 14.beta.-hydroxy-paclitaxel analogues which show excellent cytotoxicity against human ovaries, lungs, colon and breast cancer cell hives [ref. J. Med. Chem. 1977, 40, 267-278]. Several derivatives show manifold better activity than those of paclitaxel and docetaxel.
14.beta.-OH-10-deacetyl baccatin-III is represented by the structural formula shown in the accompanying drawing.
Prior Art References
In this field, European Patent No.0 559 019 A1 relates to isolation of 14-beta-hydroxy-10-deacetyl-baccatin III. However, the above process involves a tedious step of chromatography which adds to the cost of the process in comparison to the present process.
Another prior U.S. Pat. No. 5,453,520 discloses preparation of 14-beta-hydroxy-10-deacetylbaccatin III and its derivatives as antitumor agents. However, this Patent discloses alcoholic extraction of Taxus wallichiana leaves and does not disclose the novel sequence of isolating 14-beta-hydroxy-10-deacetyl-baccatin III including the selective crystallisation employed in the present invention.
Yet another Patent No. WO 9629321 A1 discloses 10-deacetylbaccatin III and 14.-beta.-hydroxy 10-deacetyl baccatin III derivatives and pharmaceutical compositions containing them. However, the above patent does not indicate or even envisage the novel sequence of steps including selective crystallisation claimed in the present invention.
Still another Patent No. EP 559019 A1 discloses preparation of 14-.beta-hydroxy-10-deacetylbaccatin III and its derivatives as antitumor agents. However, the process defined in the above patent is different and involves a costly and tedious chromatographic technique which is not employed in the present invention.
In fact, the applicants have identified that the presence of an additional C-14 hydroxyl group in 14.beta.-OH-10-DAB is found to provide much higher solubility in protic solvents than the usual 10-DAB-III. Hence, the taxoids derived from 14.beta.-OH-10-DAB have substantially improved solubility, bioavailability and hydrophilicity related drug resistance.
As such, the derivatives of 14.beta.-hydroxy-10-deacetyl baccatin-III are expected to have substantially improved water solubility with consequent advantages in connection with administration by perfusion in humans of antitumour drugs containing this type of diterpenic nucleus.